In general, immune system in our body will protect us from infection or carcinogenesis through recognizing and eliminating foreign pathogens, such as bacteria and viruses, or pre-cancerous and cancerous cells. Immune checkpoint molecules including programmed cell death 1 (PD-1) and its ligand (PD-L1) have been revealed to promote cancer survival by suppressing the function of immune cells, especially cytotoxic T cells (CTLs). Recently, immune checkpoint blockade antibody therapies against PD-1 or PD-L1 have been widely used and shown remarkable tumor shrinkage or durable disease control in various cancer. However, therapeutic resistance after initial response is increasingly observed, and the mechanisms underlying anti-PD-L1 blockade antibody (aPD-L1) treatment have not been clarified yet.

In current study, we identified two unique secreted PD-L1 splicing variants from aPD-L1-resistant NSCLC patients. These secreted PD-L1 variants worked as “decoys” of aPD-L1 antibody in HLA-matched co-culture system of iPSC-derived CD8 T cells and cancer cells. Importantly, expression of secreted PD-L1 variant in cancer cells induced an accumulation of soluble PD-L1 in plasma, and mediated therapeutic resistance to PD-L1 blockade in the MC38 syngeneic mice model (Figure 1). Moreover, PD-1 blockade antibody but not PD-L1 antibody retained its inhibitory activity in the presence of secreted PD-L1 variants. These results suggested that the anti-PD-1 antibody might overcome the secreted PD-L1 variant–induced resistance in vitro and in vivo.

Our finding revealed novel mechanisms for the resistance to PD-L1 blockade antibodies and anti-PD-1 treatment could be a therapeutic option to overcome the resistance mediated by secreted PD-L1 variants (Figure 2).